The HIV-related mortality and morbidity has been significantly reduced by highly active antiretroviral therapy (HAART) because majority of the individuals receiving HAART develop undetectable viral RNA in plasma (<50 copies/ml). However HAART has been unable to eradicate the virus because virus hides in the deep lymphoid tissues and upon withdrawal of therapy, virus reappears in most of these individuals, with renewed attack on the CD4+T cell population. This viral resurgence poses another challenge to develop strategies to control virus replication in those patients who for some reason opt for treatment withdrawal. One attractive approach for the containment of virus is "therapeutic immunization". We have chosen a neuropathogenic model of HIV/AIDS in rhesus macaques that has been developed by infecting macaques with SIV/17E-Fr and SIVdeltaB670. This model has been shown to develop SIV-induced AIDS and dementia in more than half of the infected animals. Studies are underway to find out effect of short term antiretroviral therapy on virus replication in blood and cerebral compartment and also the nature of resurgent virus after cessation of antiretroviral therapy. In this application we will investigate whether a vaccine given during the period of drug therapy could induce protective immunity that would prevent virus from resurgence or significantly lower the rate of viral replication and delay the onset of clinical disease for indefinite time. In view of our work as well as work from several other laboratories that live attenuated vaccine confers best protection in SIV/SHIV macaque model of AIDS, we will use a live attenuated vaccine to test the concept of therapeutic immunization. We will inoculate the macaques with SIV/R71-Fr and SIVdeltaB670 and treat them with an antiretroviral (PMPA). A group of macaques will be immunized with live attenuated virus whereas another unvaccinated group will serve as controls. We will monitor viral resurgence, cellular and humoral immune responses, emergence of drug resistance and progression to clinical phase of the disease in these two groups and determine whether a therapeutic vaccine confers significant advantage. In anticipation of success, we will then determine whether a relatively safer therapeutic immunogen, inactivated virus particles, could also elicit similar effect. These studies will establish proof-of- concept for the therapeutic immunization. If successful, this vaccine approach would also provide an alternative to the dreary prospect of permanent post-infection drug therapy.